The objective of this project is to determine the role of ?-3 derived epoxy fatty acid (?-3 epoxides) and soluble epoxide hydrolase (sEH) in mutant Kras/pancreatitis-induced carcinogenesis and to establish an efficient strategy for the prevention of pancreatic cancer using ?-3 polyunsaturated fatty acids (PUFAs) and small molecular sEH inhibitors. Anti-inflammatory/carcinogenic effects of ?-3 PUFAs are well known; but the mechanism/s remains unclear. Of the three main metabolic pathways (COX, LOX, and CYP), ?-3 PUFAs are predominantly metabolized by CYP epoxygenase/s, leading to an accumulation of ?-3 epoxy fatty acid (?-3 epoxides); and ?-3 PUFAs are poor substrates of COX and LOX. Fat1 transgenic mouse constitutively converts ?-6 to ?-3 PUFAs in all organs. Lipid metabolomics profiling in humans with ?-3 PUFAs supplementation and in Fat1 mice further demonstrate that ?-3 epoxides are major metabolites. Functional studies indicate that ?-3 epoxides are highly potent metabolites responsible for anti-inflammatory/carcinogenic actions, possibly via targeting inflammatory signals and MAP kinase. However, under physiologic conditions, these ?-3 epoxides are quickly inactivated by sEH to the diol products, and a sEH inhibitor appears crucial to stabilizing/enhancing these ?-3 epoxides actions. Thus, we hypothesize that ?-3 epoxides are the key metabolites of ?-3 PUFAs for inhibiting inflammation and carcinogenesis via targeting Kras-activated MAP kinases and inflammation signals (NF- kB and PPAR?), and that sEH inhibition is an efficient approach to enhance these ?-3 epoxides actions against pancreatitis-induced carcinogenesis. There are three specific Aims to test our hypothesis: 1) to determine a role of Fat1 transgene, sEH gene deficiency or their combination in stabilizing and enhancing ?-3 epoxides actions against mutant Kras/pancreatitis-induced carcinogenesis in PanKras mice, 2) to determine the effectiveness of the ?-3 PUFAs combined with a highly potent sEH inhibitor as an efficient chemopreventive approach against pancreatitis-induced carcinogenesis in PanKras mice, and 3) to test our hypothesis that ?-3 epoxides are the key metabolites of ?-3 PUFAs for inhibiting pancreatic cancer via targeting mutant Kras-activated signals, inflammation signals (NF-kB and PPAR?) and angiogenesis using our unique cell models and molecular biology approaches.